Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling

Abstract

Unfractionated heparin (UFH) is a widely used anticoagulant that has long been known to potentiate platelet responses to subthreshold doses of platelet agonists. UFH has been reported to bind and induce modest conformational changes in the major platelet integrin, ␣IIb␤3, and induce minor changes in platelet morphology. The mechanism by which UFH elicits these platelet-activating effects, however, is not well understood. We found that both human and murine platelets exposed to UFH, either in solution or immobilized onto artificial surfaces, underwent biochemical and morphologic changes indicative of a potentiated state, including phosphorylation of key cytosolic signaling molecules and cytoskeletal changes leading to cell spreading. Low molecular weight heparin and the synthetic pentasaccharide, fondaparinux, had similar plateletpotentiating effects. Human or mouse platelets lacking functional integrin ␣IIb␤3 complexes and human platelets pretreated with the fibrinogen receptor antagonists eptifibatide or abciximab failed to become potentiated by heparin, demonstrating that heparin promotes platelet responsiveness via its ability to initiate ␣IIb␤3-mediated outside-in signaling. Taken together, these data provide novel insights into the mechanism by which platelets become activated after exposure to heparin and heparin-coated surfaces, and suggest that currently used glycoprotein IIb-IIIa inhibitors may be effective inhibitors of nonimmune forms of heparin-induced platelet activation.

Influence of different anticoagulants on monocyte procoagulant functions and monocyte‐platelet aggregates formation

“…Heparin promotes platelet responsiveness [14], which may facilitate platelet-monocyte aggregation [2], with subsequent lowering of platelet counts seen in blood anticoagulated with heparin. The yield of freshly isolated PBMCs was 46% (40.54), 37% (31.46) and 31% (24.40) (P < 0.001 compared with EDTA) from blood anticoagulated with EDTA, citrate and heparin, respectively (FriedmanÕs test P < 0.001).…”

Frequency of heparin/platelet factor 4-dependent platelet antibodies in patients undergoing angioplasty and stenting for cardiovascular disease and their role for on-clopidogrel platelet reactivity

“…Heparin is known to induce platelet activation resulting in P-selectin expression [1]. Platelets poised for activation, or those which exhibit already some degree of activation (expressing P-selectin) are likely to respond stronger to agonists than resting platelets [46,47].…”

“…The more common type 1 of heparin-induced platelet activation results in moderate activation through association directly with the platelet surface, changing platelet morphology and induction of P-selectin expression, and conformational change of the major platelet integrin aIIb3, thus exposing the fibrinogen binding site. Recently, strong evidence was provided that heparin promotes platelet responsiveness through initiation of aIIb3 outside-in signaling [1]. Less frequently, but associated with very severe complications of heparin treatment is type 2 of heparin-induced platelet activation that results in heparin-induced thrombocytopenia (HIT).…”

Nöroendovasküler Girişimsel Tedavilerde Anti-trombotik İlaç Kullanımı

“…Heparin IV verildikten dakikalar sonra GP IIb-IIIa reseptörü üzerinden trombosit aktivasyonu yapar. Ancak bu reseptör daha önce tirofiban ile bloke edilirse, heparinin trombosit aktive etme özelliği ortadan kalkar [5].…”